a. Field of Invention
This invention relates to derivatives of the tetradecapeptide somatostatin. More particularly, this invention concerns decapeptide derivatives in which Lys.sup.4 or Asn.sup.5 is replaced with a residue of glycine, salts thereof, a process for preparing said derivatives and salts, intermediates used in the process and methods for using the decapeptide derivatives and their salts.
B. Prior Art
The name "somatostatin" has been proposed for the factor found in hypothalamic extracts which inhibits the secretion of growth hormone (somatotropin). The structure of this factor has been elucidated by P. Brazeau et al., Science, 179, 77(1973) and reported to have the following tetradecapeptide structure: ##STR2##
The constitution of the tetradecapeptide somatostatin has been confirmed by synthesis; for example, see D. Sarantakis and W. A. McKinley, Biochem. Biophys. Res. Comm., 54, 234(1973), J. Rivier et al., Compt. Rend. Ser. D, 276, 2737(1973) and H. U. Immer et al., Helv. Chim. Acta, 57, 730(1974).
The important physiological activity of this tetradecapeptide established it as a compound of significance for clinical pharmacology relating to the treatment of acromegaly and the management of diabetes; for example, see K. Lundbaek et al., Lancet, 2, 131(1970) and R. Guillemin in "Chemistry and Biology of Peptides", J. Meienhofer, Ed., 3rd American Peptide Symposium Boston 1972, Ann Arbor Science Publications, Ann Arbor, Mich., 1972.
Since the structure and physiological activity of somatostatin was determined, a number of analogs of somatostatin have been reported, for instance see the report by J. Rivier et al., in "Peptides 1976", Editions de l'Universite de Bruxelles, Brussels, Belgium, edited by A. Loffet, 1977, 99. 427-451. More specifically, a number of shortened derivatives of somatostatin have been reported, for example: Netherlands patent application Ser. No. 7,602,395 published Sept. 14, 1976, discloses compounds of the formula ##STR3## in which X is Lys, Nle or Cys and Y is Asn, Gln or Thr; Belgium Pat. No. 827,530 issued Oct. 3, 1975, discloses compounds of the formula ##STR4## in which V is Asn or Ala and W is Lys or Orn; and by H. U. Immer et al., in U.S. Pat. No. 4,020,157, issued Apr. 26, 1977, discloses compounds of the formula ##STR5## in which R is hydrogen or NHR.sup.1 wherein R.sup.1 is lower aliphatic acyl or benzoyl.
The present invention discloses novel decapeptide derivatives of somatostatin in which Lys.sup.4 or Asn.sup.5 is replaced by a residue of glycine. Thus, these derivatives differ from the reported derivatives of somatostatin by having a different arrangement of amino acids. The derivatives of this invention possess a physiological activity similar to that of somatostatin. The derivatives are prepared readily by a convenient process, which includes the following advantages: the process starts from readily available materials, avoids noxious reagents, is executed facilely and utilizes easily removable protecting groups.
The foregoing advantages and attributes render the peptides of this invention useful for the management of diabetes and for the treatment of acromegaly.